{"gene":"ALDOB","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2020,"finding":"ALDOB forms a protein complex with Akt and protein phosphatase 2A (PP2A), acting as a scaffold that recruits PP2A to dephosphorylate phosphorylated Akt (p-Akt), thereby suppressing Akt activity and tumor growth; this scaffolding function is independent of ALDOB's enzymatic activity, as demonstrated by the R304A mutant (which disrupts Aldob/Akt interaction) restoring Akt activity.","method":"Co-immunoprecipitation, mutagenesis (R304A), xenograft mouse models, loss-of-function experiments, cell viability/cycle/glucose uptake assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex, active-site-independent mutagenesis validating scaffolding role, in vivo xenograft validation, multiple orthogonal methods in single rigorous study","pmids":["33275593"],"is_preprint":false},{"year":2023,"finding":"ALDOB translocates to the nucleus and interacts with lysine acetyltransferase 2A (KAT2A), leading to inhibition of H3K9 acetylation at the TGFB1 promoter and thereby suppressing TGFB1 transcription; loss of ALDOB in tumor cells upregulates TGF-β, increases Treg cells, and impairs CD8+ T cell activity.","method":"Co-immunoprecipitation, ChIP assay, nuclear fractionation/localization experiments, ALDOB knockout/knockdown mouse models, subcutaneous tumor models, combinatorial antibody blockade experiments","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — nuclear localization confirmed by fractionation, protein interaction by Co-IP, epigenetic mechanism by ChIP, functional consequence validated in vivo with multiple orthogonal methods","pmids":["38051951"],"is_preprint":false},{"year":2023,"finding":"In pancreatic cancer, low ALDOB expression combined with high GLUT1 leads to increased glycolytic flux and elevated G6PD activity driving pentose phosphate pathway and pyrimidine biosynthesis; increasing ALDOB expression reverses these metabolic phenotypes and chemotherapy resistance.","method":"PDAC organoid metabolomics, ALDOB gain-of-function experiments, GLUT1 inhibition, G6PD activity assays, glucose metabolism flux measurements","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function rescue with metabolic flux readouts in organoid models, single lab, two orthogonal metabolic methods","pmids":["37597521"],"is_preprint":false},{"year":2014,"finding":"ALDOB binds directly to hepatitis B surface antigen (HBsAg S region); co-existence of HBsAg and ALDOB in the cytoplasm enhances AKT and GSK-3β phosphorylation, decreases pro-apoptotic proteins (Bax, Bid, Bim, Puma), and increases pro-survival proteins (Bcl-2, Bcl-xl, Mcl-1), inhibiting cisplatin-induced apoptosis in HepG2 cells.","method":"Yeast 2-hybrid, Co-immunoprecipitation (endogenous and exogenous), co-localization by immunofluorescence, western blot for apoptosis pathway proteins","journal":"Critical reviews in eukaryotic gene expression","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding confirmed by Co-IP (endogenous + exogenous), functional apoptosis assay with pathway readout, single lab","pmids":["25072145"],"is_preprint":false},{"year":2016,"finding":"Fructose activates ChREBP (by inducing cytosol-to-nucleus translocation) and inactivates FoxO1/3α (by promoting nucleus-to-cytosol shuttling via Akt1-mediated phosphorylation) to up-regulate ALDOB expression in vascular smooth muscle cells; ALDOB knockdown prevents fructose-induced methylglyoxal (MG) overproduction and VSMC proliferation.","method":"Western blotting, real-time PCR, ChREBP/FoxO1/3α knockdown (siRNA), Akt1 inhibitor, nuclear/cytosolic fractionation, ChREBP promoter binding assay, fructose-fed mouse model","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (MG production, proliferation), transcription factor nuclear translocation confirmed, multiple orthogonal methods, single lab","pmids":["28007970"],"is_preprint":false},{"year":2024,"finding":"DUSP4 interacts with ALDOB and inhibits G6PD activity via ALDOB dephosphorylation, thereby elevating ROS levels and enhancing therapeutic sensitivity in HER2-positive breast cancer.","method":"Immunoprecipitation and mass spectrometry (IP-MS), RT-qPCR, IC50 assays, DUSP4 knockout cells","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction established by IP-MS, functional dephosphorylation of ALDOB with downstream G6PD activity readout, single lab","pmids":["38843658"],"is_preprint":false},{"year":2024,"finding":"SUV39H1 negatively regulates ALDOB expression by depositing H3K9me3 at the ALDOB promoter region; SUV39H1 knockdown reduces H3K9me3 modification at the ALDOB promoter, increases ALDOB expression, and inhibits gastric cancer cell proliferation, migration, and invasion.","method":"ChIP assay, RT-qPCR, western blot, siRNA knockdown, enzymatic inhibitors (chaetocin, F5446), xenograft experiment","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay directly demonstrating H3K9me3 at ALDOB promoter, rescue experiments confirming pathway, single lab","pmids":["39302619"],"is_preprint":false},{"year":2024,"finding":"In aldolase B deficient (Aldob-/-) mice, fructose 1-phosphate (F1P) accumulation stimulates hepatic de novo lipogenesis (DNL) via two mediators: glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP); ChREBP knockdown normalized mRNA expression of DNL enzymes and reduced fractional DNL, while Gckr knockout reduced de novo palmitate synthesis, but neither intervention reduced intrahepatic triglyceride levels.","method":"Aldob-/- mouse model crossed with Gckr-/- mice, shRNA against ChREBP, stable isotope tracing for DNL, hepatic mRNA expression analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double-knockout mouse model, stable isotope tracing for DNL quantification, multiple orthogonal interventions, single lab","pmids":["38372975"],"is_preprint":false},{"year":2025,"finding":"FDFT1 downregulation decreases cholesterol and bile acid levels, which increases HNF4A transcriptional activity; HNF4A binds the ALDOB promoter to promote ALDOB transcription; ALDOB then binds AKT1 and inhibits AKT1 phosphorylation, delaying hepatocellular carcinoma progression.","method":"ChIP assay (HNF4A binding to ALDOB promoter), co-immunoprecipitation (ALDOB-AKT1), FDFT1 knockdown/overexpression, AKT inhibitor combination experiments, in vitro and in vivo models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for promoter binding, Co-IP for protein interaction, functional rescue with AKT inhibitor, single lab with multiple orthogonal methods","pmids":["39899681"],"is_preprint":false},{"year":2025,"finding":"FOXP3 acts as a transcription factor that directly binds the ALDOB promoter and activates ALDOB transcription; this regulation is upstream-controlled by METTL14-mediated m6A modification of FOXP3 mRNA (via IGF2BP1-dependent stabilization), linking RNA methylation to ALDOB expression and suppression of HCC glycolysis.","method":"Dual luciferase reporter assay, ChIP assay (FOXP3 binding to ALDOB promoter), MeRIP assay (m6A on FOXP3), RIP assay (METTL14/IGF2BP1 interaction with FOXP3), xenograft mouse models","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP and luciferase reporter, m6A modification by MeRIP, multiple orthogonal methods, single lab","pmids":["40778958"],"is_preprint":false},{"year":2026,"finding":"ALDOB is lactylated at lysine 87 (K87) under hypoxic conditions; K87 lactylation amplifies glycolytic flux and recruits DRP1 to mitochondria via SENP3-mediated deSUMOylation of DRP1, facilitating mitochondrial fragmentation and driving pulmonary artery smooth muscle cell proliferation, migration, and phenotypic switching in pulmonary hypertension; SIRT1 acts as the delactylase for ALDOB-K87.","method":"Lactylomic profiling, ALDOB lactylation-mimetic and -deficient mutants, DRP1 co-immunoprecipitation, SENP3 functional assays, rodent PH models, genetic/pharmacological suppression of ALDOB lactylation in vivo","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM identified by proteomics, validated by mutagenesis mimetics, protein interaction by Co-IP, in vivo disease model validation, single lab","pmids":["41896623"],"is_preprint":false},{"year":2025,"finding":"ALDOB overexpression in colorectal cancer enhances WNT signaling pathway-related proteins (β-catenin and c-myc), which promotes PDL1 expression in CRC cells, thereby inhibiting CD8+ T cell proliferation and killing activity in co-culture systems.","method":"ALDOB overexpression, western blot for β-catenin/c-myc/PDL1, co-culture assays with CD8+ T cells, flow cytometry","journal":"Immunology and cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach with downstream pathway western blot, no mechanistic resolution of how ALDOB engages WNT components","pmids":["39909069"],"is_preprint":false},{"year":2023,"finding":"ALDOB inhibition in hepatocellular carcinoma promotes upregulation of Ki67 and significantly enhances glycolytic activity, as well as proliferation, invasion, and migration of HCC cells; these effects are further amplified under hypoxic conditions, establishing ALDOB as a suppressor of glycolytic-driven malignant HCC behavior.","method":"ALDOB siRNA knockdown and overexpression in hepatoma cell lines, glycolytic activity assays, proliferation/invasion/migration assays under normoxia and hypoxia, in vivo animal tumor models","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined metabolic and cellular phenotypes, in vivo validation, single lab","pmids":["36749124"],"is_preprint":false},{"year":2026,"finding":"FOXA2 transcriptionally activates ALDOB expression by binding the ALDOB promoter, enhancing fatty acid β-oxidation and suppressing irinotecan sensitivity in colorectal cancer; ALDOB overexpression restores drug resistance in FOXA2-inhibited cells.","method":"Dual-luciferase reporter assay, ChIP assay (FOXA2 binding to ALDOB promoter), FOXA2 knockdown/overexpression, ALDOB overexpression rescue, fatty acid β-oxidation rate assays, xenograft tumor model","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP and luciferase, functional rescue with ALDOB overexpression, single lab with multiple orthogonal methods","pmids":["41513047"],"is_preprint":false},{"year":2010,"finding":"Recombinant ALDOB variants p.R46W and p.Y343H show particularly impaired residual catalytic activity toward fructose-1-phosphate (F1P), establishing these residues as functionally important for enzymatic activity in aldolase B.","method":"Recombinant protein expression, enzymatic activity assay toward F1P","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with recombinant mutant proteins directly measuring catalytic activity, single lab","pmids":["20848650"],"is_preprint":false}],"current_model":"ALDOB is a fructose-1,6-bisphosphate aldolase that suppresses tumor growth through both enzymatic and non-enzymatic mechanisms: it forms a scaffold complex with Akt and PP2A to promote dephosphorylation and inactivation of p-Akt (independent of catalytic activity), translocates to the nucleus to interact with KAT2A and inhibit H3K9 acetylation at the TGFB1 promoter (suppressing immune evasion), and its expression is regulated epigenetically by SUV39H1-mediated H3K9me3 and transcriptionally by FOXP3, HNF4A, and FOXA2; additionally, ALDOB is post-translationally modified by lactylation at K87 (erased by SIRT1), which recruits DRP1 via SENP3-mediated deSUMOylation to drive mitochondrial fission, while in vascular tissue fructose-driven ChREBP activation and FoxO1/3α inactivation upregulate ALDOB to increase methylglyoxal production and vascular remodeling."},"narrative":{"mechanistic_narrative":"ALDOB is a fructose-1,6-bisphosphate aldolase whose catalytic handling of fructose metabolites and whose moonlighting protein-scaffold functions converge on a role as a metabolic gatekeeper and tumor suppressor [PMID:33275593, PMID:20848650]. Enzymatically it cleaves fructose-1-phosphate, an activity that depends on residues including R46 and Y343 [PMID:20848650]; loss of this metabolic control allows F1P accumulation that drives hepatic de novo lipogenesis through GKRP and ChREBP [PMID:38372975], and in vascular smooth muscle cells fructose-driven ChREBP activation with FoxO1/3α inactivation upregulates ALDOB to increase methylglyoxal output and proliferation [PMID:28007970]. Beyond catalysis, ALDOB acts as a scaffold that recruits PP2A to dephosphorylate and inactivate Akt independent of enzymatic activity, an interaction abolished by the R304A mutant and suppressing tumor growth [PMID:33275593, PMID:39899681]. ALDOB also translocates to the nucleus, where it binds KAT2A to limit H3K9 acetylation at the TGFB1 promoter, repressing TGF-β and restraining Treg-mediated suppression of CD8+ T cells [PMID:38051951]. Across hepatocellular, pancreatic, and gastric cancers, low ALDOB raises glycolytic flux, G6PD-driven pentose phosphate activity, and proliferation, identifying it as a suppressor of glycolytic malignancy [PMID:37597521, PMID:39302619, PMID:36749124]. ALDOB expression is set epigenetically by SUV39H1-deposited H3K9me3 and transcriptionally by HNF4A, FOXP3, and FOXA2 [PMID:39302619, PMID:39899681, PMID:40778958, PMID:41513047]. Under hypoxia, ALDOB is lactylated at K87 (erased by SIRT1), which recruits DRP1 via SENP3-mediated deSUMOylation to promote mitochondrial fission and smooth muscle proliferation in pulmonary hypertension [PMID:41896623].","teleology":[{"year":2010,"claim":"Established which residues are required for ALDOB catalytic activity, defining the enzymatic basis later contrasted against non-catalytic moonlighting roles.","evidence":"Recombinant ALDOB variants assayed for F1P-cleaving activity in vitro","pmids":["20848650"],"confidence":"Medium","gaps":["Does not address substrate handling of fructose-1,6-bisphosphate","No structural model of the active site provided","No in vivo phenotype linked to these specific variants"]},{"year":2014,"claim":"First evidence that ALDOB engages a viral partner and influences survival signaling, hinting at non-metabolic protein-interaction functions.","evidence":"Yeast 2-hybrid and Co-IP of ALDOB with HBsAg, apoptosis pathway western blots in HepG2 cells","pmids":["25072145"],"confidence":"Medium","gaps":["Mechanism by which the complex modulates Akt/GSK-3β phosphorylation unresolved","Direct vs indirect effect on Bcl-2 family proteins not separated","Single cell line"]},{"year":2016,"claim":"Showed that fructose-responsive transcription factors set ALDOB levels to control downstream methylglyoxal production, linking ALDOB to vascular remodeling.","evidence":"siRNA knockdown of ChREBP/FoxO, Akt1 inhibition, nuclear fractionation, fructose-fed mouse model","pmids":["28007970"],"confidence":"Medium","gaps":["Direct promoter occupancy of ChREBP at ALDOB not fully resolved","Contribution of ALDOB enzymatic activity to MG production not isolated","Single lab"]},{"year":2020,"claim":"Defined ALDOB's catalysis-independent scaffolding role: it recruits PP2A to dephosphorylate p-Akt, establishing a tumor-suppressive non-enzymatic mechanism.","evidence":"Reciprocal Co-IP, R304A interaction-disrupting mutant, xenograft models, viability/glucose-uptake assays","pmids":["33275593"],"confidence":"High","gaps":["Structural basis of the ALDOB-Akt-PP2A scaffold unknown","Determinants of complex assembly beyond R304 unmapped","Tissue specificity of the scaffold not defined"]},{"year":2023,"claim":"Revealed a nuclear, chromatin-directed function for ALDOB, connecting it to immune evasion through KAT2A and TGFB1 repression.","evidence":"Co-IP, ChIP at TGFB1 promoter, nuclear fractionation, ALDOB knockout mouse tumor models, antibody blockade","pmids":["38051951"],"confidence":"High","gaps":["Signal triggering nuclear translocation of ALDOB unknown","Whether KAT2A inhibition is direct enzymatic interference unresolved","Genome-wide chromatin targets beyond TGFB1 not mapped"]},{"year":2023,"claim":"Demonstrated that low ALDOB reprograms glycolysis and the pentose phosphate pathway to confer chemoresistance, generalizing its tumor-suppressive metabolic role across cancers.","evidence":"PDAC organoid metabolomics, ALDOB gain-of-function rescue, GLUT1 inhibition, G6PD assays; parallel HCC siRNA/overexpression with glycolytic and invasion assays","pmids":["37597521","36749124"],"confidence":"Medium","gaps":["Whether metabolic effects require ALDOB catalysis vs scaffold function not separated","Mechanism linking ALDOB loss to G6PD elevation incomplete","Single-lab organoid systems"]},{"year":2024,"claim":"Identified epigenetic and post-translational layers controlling ALDOB: SUV39H1-mediated H3K9me3 silencing, DUSP4-mediated dephosphorylation, and F1P-driven lipogenesis in its absence.","evidence":"ChIP for H3K9me3 at ALDOB promoter with rescue; IP-MS of DUSP4-ALDOB with G6PD readout; Aldob-/-;Gckr-/- mice with ChREBP knockdown and isotope tracing","pmids":["39302619","38843658","38372975"],"confidence":"Medium","gaps":["Site of ALDOB phosphorylation targeted by DUSP4 not defined","GKRP/ChREBP interventions did not reduce intrahepatic triglyceride, leaving lipid phenotype partly unexplained","Cross-tissue generality of SUV39H1 silencing untested"]},{"year":2025,"claim":"Mapped the upstream transcriptional network activating ALDOB (HNF4A, FOXP3, FOXA2) and tied it to suppression of glycolysis, drug response, and Akt inhibition.","evidence":"ChIP and dual-luciferase promoter assays for HNF4A/FOXP3/FOXA2; Co-IP of ALDOB-AKT1; MeRIP/RIP for m6A control of FOXP3; rescue and xenograft models","pmids":["39899681","40778958","41513047"],"confidence":"Medium","gaps":["Relative contribution of each transcription factor in a given tissue unresolved","Whether these regulators act combinatorially not tested","FOXA2-driven β-oxidation link to ALDOB enzymatic function not isolated"]},{"year":2026,"claim":"Discovered hypoxia-induced K87 lactylation as a modification that couples ALDOB to mitochondrial fission machinery, expanding its role into pulmonary hypertension.","evidence":"Lactylomic profiling, lactylation-mimetic/-deficient mutants, DRP1 Co-IP, SENP3 assays, SIRT1 delactylase identification, rodent PH models","pmids":["41896623"],"confidence":"Medium","gaps":["How K87 lactylation mechanistically promotes DRP1 recruitment unresolved","Whether this PTM affects the Akt/PP2A scaffold function unknown","Single-lab disease model"]},{"year":null,"claim":"It remains unresolved how ALDOB's enzymatic activity, cytoplasmic scaffolding of Akt/PP2A, and nuclear chromatin functions are coordinately controlled within a single cell and which is dominant in defined tissue contexts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating catalytic and scaffold conformations","Signals partitioning ALDOB between cytoplasm, nucleus, and mitochondria undefined","Catalysis-dependent vs -independent contributions to tumor suppression not cleanly separated across cancers"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,7,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,12]}],"complexes":[],"partners":["AKT1","PP2A","KAT2A","DUSP4","DRP1","HBSAG"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05062","full_name":"Fructose-bisphosphate aldolase B","aliases":["Liver-type aldolase"],"length_aa":364,"mass_kda":39.5,"function":"Catalyzes the aldol cleavage of fructose 1,6-biphosphate to form two triosephosphates dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in glycolysis as well as the reverse stereospecific aldol addition reaction in gluconeogenesis. In fructolysis, metabolizes fructose 1-phosphate derived from the phosphorylation of dietary fructose by fructokinase into dihydroxyacetone phosphate and D-glyceraldehyde (PubMed:10970798, PubMed:12205126, PubMed:20848650). Acts as an adapter independently of its enzymatic activity, exerts a tumor suppressor role by stabilizing the ternary complex with G6PD and TP53 to inhibit G6PD activity and keep oxidative pentose phosphate metabolism in check (PubMed:35122041)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite","url":"https://www.uniprot.org/uniprotkb/P05062/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALDOB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ALDOB","total_profiled":1310},"omim":[{"mim_id":"612724","title":"ALDOLASE B, FRUCTOSE-BISPHOSPHATE; ALDOB","url":"https://www.omim.org/entry/612724"},{"mim_id":"611153","title":"XPA, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPA","url":"https://www.omim.org/entry/611153"},{"mim_id":"602938","title":"BILE ACID CoA:AMINO ACID N-ACYLTRANSFERASE; BAAT","url":"https://www.omim.org/entry/602938"},{"mim_id":"600281","title":"HEPATOCYTE NUCLEAR FACTOR 4-ALPHA; HNF4A","url":"https://www.omim.org/entry/600281"},{"mim_id":"229600","title":"FRUCTOSE INTOLERANCE, HEREDITARY; HFI","url":"https://www.omim.org/entry/229600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":5987.0},{"tissue":"kidney","ntpm":6695.1},{"tissue":"liver","ntpm":10467.2}],"url":"https://www.proteinatlas.org/search/ALDOB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P05062","domains":[{"cath_id":"3.20.20.70","chopping":"9-338","consensus_level":"high","plddt":97.8336,"start":9,"end":338}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05062","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05062-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05062-F1-predicted_aligned_error_v6.png","plddt_mean":96.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALDOB","jax_strain_url":"https://www.jax.org/strain/search?query=ALDOB"},"sequence":{"accession":"P05062","fasta_url":"https://rest.uniprot.org/uniprotkb/P05062.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05062/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05062"}},"corpus_meta":[{"pmid":"37597521","id":"PMC_37597521","title":"Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer.","date":"2023","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37597521","citation_count":73,"is_preprint":false},{"pmid":"33275593","id":"PMC_33275593","title":"Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex.","date":"2020","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/33275593","citation_count":55,"is_preprint":false},{"pmid":"15880727","id":"PMC_15880727","title":"The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe.","date":"2005","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15880727","citation_count":42,"is_preprint":false},{"pmid":"38051951","id":"PMC_38051951","title":"ALDOB/KAT2A interactions epigenetically modulate TGF-β expression and T cell functions in hepatocellular carcinogenesis.","date":"2023","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/38051951","citation_count":34,"is_preprint":false},{"pmid":"39899681","id":"PMC_39899681","title":"Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39899681","citation_count":20,"is_preprint":false},{"pmid":"20848650","id":"PMC_20848650","title":"Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion.","date":"2010","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/20848650","citation_count":20,"is_preprint":false},{"pmid":"28007970","id":"PMC_28007970","title":"Dual effects of fructose on ChREBP and FoxO1/3α are responsible for AldoB up-regulation and vascular remodelling.","date":"2016","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/28007970","citation_count":15,"is_preprint":false},{"pmid":"37576390","id":"PMC_37576390","title":"ALDOB plays a tumor-suppressive role by inhibiting AKT activation in gastric cancer.","date":"2023","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37576390","citation_count":13,"is_preprint":false},{"pmid":"36749124","id":"PMC_36749124","title":"Down-regulation of ALDOB during metabolic reprogramming mediates malignant behavior in hepatocellular carcinoma and insensitivity to postoperative adjuvant transarterial chemoembolization.","date":"2023","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/36749124","citation_count":9,"is_preprint":false},{"pmid":"7486251","id":"PMC_7486251","title":"Sheep gene mapping: assignment of ALDOB, CYP19, WT and SOX2 by somatic cell hybrid analysis.","date":"1995","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7486251","citation_count":8,"is_preprint":false},{"pmid":"38778508","id":"PMC_38778508","title":"MRTO4 Enhances Glycolysis to Facilitate HCC Progression by Inhibiting ALDOB.","date":"2024","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/38778508","citation_count":7,"is_preprint":false},{"pmid":"22375183","id":"PMC_22375183","title":"A Novel Frameshift Mutation of the ALDOB Gene in a Korean Girl Presenting with Recurrent Hepatitis Diagnosed as Hereditary Fructose Intolerance.","date":"2012","source":"Gut and liver","url":"https://pubmed.ncbi.nlm.nih.gov/22375183","citation_count":7,"is_preprint":false},{"pmid":"25072145","id":"PMC_25072145","title":"ALDOB acts as a novel HBsAg-binding protein and its coexistence inhibits cisplatin-induced HepG2 cell apoptosis.","date":"2014","source":"Critical reviews in eukaryotic gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/25072145","citation_count":6,"is_preprint":false},{"pmid":"38972375","id":"PMC_38972375","title":"Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency.","date":"2024","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38972375","citation_count":4,"is_preprint":false},{"pmid":"38843658","id":"PMC_38843658","title":"DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38843658","citation_count":4,"is_preprint":false},{"pmid":"39909069","id":"PMC_39909069","title":"ALDOB suppresses the activity of CD8+ T cells in colorectal cancer via the WNT signaling pathway.","date":"2025","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39909069","citation_count":4,"is_preprint":false},{"pmid":"37743645","id":"PMC_37743645","title":"Associations between ALDOB polymorphisms and intrahepatic cholestasis of pregnancy susceptibility in the Chinese Han population.","date":"2023","source":"Ginekologia polska","url":"https://pubmed.ncbi.nlm.nih.gov/37743645","citation_count":1,"is_preprint":false},{"pmid":"36659819","id":"PMC_36659819","title":"Identification of a novel mutation in the ALDOB gene in hereditary fructose intolerance.","date":"2023","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/36659819","citation_count":1,"is_preprint":false},{"pmid":"40778958","id":"PMC_40778958","title":"Mechanism of METTL14 regulates HBV-HCC malignant progression by mediating m6A modification of FOXP3 and thus transcriptional activation of ALDOB.","date":"2025","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/40778958","citation_count":1,"is_preprint":false},{"pmid":"39302619","id":"PMC_39302619","title":"SUV39H1 Regulates Gastric Cancer Progression via the H3K9me3/ALDOB Axis.","date":"2024","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39302619","citation_count":1,"is_preprint":false},{"pmid":"38820866","id":"PMC_38820866","title":"Characterization of a human induced pluripotent stem cell line (FDCHi015-A) derived from PBMCs of a patient harbouring ALDOB mutation.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38820866","citation_count":1,"is_preprint":false},{"pmid":"41896623","id":"PMC_41896623","title":"ALDOB K87 lactylation drives mitochondrial fission and metabolic reprogramming in pulmonary hypertension.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41896623","citation_count":1,"is_preprint":false},{"pmid":"38802922","id":"PMC_38802922","title":"Multi-omics analysis of a case of congenital microtia reveals aldob and oxidative stress associated with microtia etiology.","date":"2024","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38802922","citation_count":1,"is_preprint":false},{"pmid":"41513047","id":"PMC_41513047","title":"FOXA2/ALDOB axis modulation of fatty acid beta-oxidation influences irinotecan resistance in colorectal cancer.","date":"2026","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41513047","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.08.674441","title":"Proteomics profiling of serum and liver in GSD Ia and Ib patients: insights into complication mechanisms and circulation biomarkers","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.674441","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.04.621970","title":"Single Cell Transcriptomics Reveal Genomic Indicators of Nonalcoholic Fatty Liver Disease","date":"2024-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.04.621970","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15447,"output_tokens":4141,"usd":0.054228,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12105,"output_tokens":3813,"usd":0.077925,"stage2_stop_reason":"end_turn"},"total_usd":0.132153,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"ALDOB forms a protein complex with Akt and protein phosphatase 2A (PP2A), acting as a scaffold that recruits PP2A to dephosphorylate phosphorylated Akt (p-Akt), thereby suppressing Akt activity and tumor growth; this scaffolding function is independent of ALDOB's enzymatic activity, as demonstrated by the R304A mutant (which disrupts Aldob/Akt interaction) restoring Akt activity.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (R304A), xenograft mouse models, loss-of-function experiments, cell viability/cycle/glucose uptake assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex, active-site-independent mutagenesis validating scaffolding role, in vivo xenograft validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33275593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOB translocates to the nucleus and interacts with lysine acetyltransferase 2A (KAT2A), leading to inhibition of H3K9 acetylation at the TGFB1 promoter and thereby suppressing TGFB1 transcription; loss of ALDOB in tumor cells upregulates TGF-β, increases Treg cells, and impairs CD8+ T cell activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, nuclear fractionation/localization experiments, ALDOB knockout/knockdown mouse models, subcutaneous tumor models, combinatorial antibody blockade experiments\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — nuclear localization confirmed by fractionation, protein interaction by Co-IP, epigenetic mechanism by ChIP, functional consequence validated in vivo with multiple orthogonal methods\",\n      \"pmids\": [\"38051951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In pancreatic cancer, low ALDOB expression combined with high GLUT1 leads to increased glycolytic flux and elevated G6PD activity driving pentose phosphate pathway and pyrimidine biosynthesis; increasing ALDOB expression reverses these metabolic phenotypes and chemotherapy resistance.\",\n      \"method\": \"PDAC organoid metabolomics, ALDOB gain-of-function experiments, GLUT1 inhibition, G6PD activity assays, glucose metabolism flux measurements\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function rescue with metabolic flux readouts in organoid models, single lab, two orthogonal metabolic methods\",\n      \"pmids\": [\"37597521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ALDOB binds directly to hepatitis B surface antigen (HBsAg S region); co-existence of HBsAg and ALDOB in the cytoplasm enhances AKT and GSK-3β phosphorylation, decreases pro-apoptotic proteins (Bax, Bid, Bim, Puma), and increases pro-survival proteins (Bcl-2, Bcl-xl, Mcl-1), inhibiting cisplatin-induced apoptosis in HepG2 cells.\",\n      \"method\": \"Yeast 2-hybrid, Co-immunoprecipitation (endogenous and exogenous), co-localization by immunofluorescence, western blot for apoptosis pathway proteins\",\n      \"journal\": \"Critical reviews in eukaryotic gene expression\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding confirmed by Co-IP (endogenous + exogenous), functional apoptosis assay with pathway readout, single lab\",\n      \"pmids\": [\"25072145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fructose activates ChREBP (by inducing cytosol-to-nucleus translocation) and inactivates FoxO1/3α (by promoting nucleus-to-cytosol shuttling via Akt1-mediated phosphorylation) to up-regulate ALDOB expression in vascular smooth muscle cells; ALDOB knockdown prevents fructose-induced methylglyoxal (MG) overproduction and VSMC proliferation.\",\n      \"method\": \"Western blotting, real-time PCR, ChREBP/FoxO1/3α knockdown (siRNA), Akt1 inhibitor, nuclear/cytosolic fractionation, ChREBP promoter binding assay, fructose-fed mouse model\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (MG production, proliferation), transcription factor nuclear translocation confirmed, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"28007970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUSP4 interacts with ALDOB and inhibits G6PD activity via ALDOB dephosphorylation, thereby elevating ROS levels and enhancing therapeutic sensitivity in HER2-positive breast cancer.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry (IP-MS), RT-qPCR, IC50 assays, DUSP4 knockout cells\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction established by IP-MS, functional dephosphorylation of ALDOB with downstream G6PD activity readout, single lab\",\n      \"pmids\": [\"38843658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUV39H1 negatively regulates ALDOB expression by depositing H3K9me3 at the ALDOB promoter region; SUV39H1 knockdown reduces H3K9me3 modification at the ALDOB promoter, increases ALDOB expression, and inhibits gastric cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"ChIP assay, RT-qPCR, western blot, siRNA knockdown, enzymatic inhibitors (chaetocin, F5446), xenograft experiment\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay directly demonstrating H3K9me3 at ALDOB promoter, rescue experiments confirming pathway, single lab\",\n      \"pmids\": [\"39302619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In aldolase B deficient (Aldob-/-) mice, fructose 1-phosphate (F1P) accumulation stimulates hepatic de novo lipogenesis (DNL) via two mediators: glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP); ChREBP knockdown normalized mRNA expression of DNL enzymes and reduced fractional DNL, while Gckr knockout reduced de novo palmitate synthesis, but neither intervention reduced intrahepatic triglyceride levels.\",\n      \"method\": \"Aldob-/- mouse model crossed with Gckr-/- mice, shRNA against ChREBP, stable isotope tracing for DNL, hepatic mRNA expression analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double-knockout mouse model, stable isotope tracing for DNL quantification, multiple orthogonal interventions, single lab\",\n      \"pmids\": [\"38372975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FDFT1 downregulation decreases cholesterol and bile acid levels, which increases HNF4A transcriptional activity; HNF4A binds the ALDOB promoter to promote ALDOB transcription; ALDOB then binds AKT1 and inhibits AKT1 phosphorylation, delaying hepatocellular carcinoma progression.\",\n      \"method\": \"ChIP assay (HNF4A binding to ALDOB promoter), co-immunoprecipitation (ALDOB-AKT1), FDFT1 knockdown/overexpression, AKT inhibitor combination experiments, in vitro and in vivo models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for promoter binding, Co-IP for protein interaction, functional rescue with AKT inhibitor, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39899681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXP3 acts as a transcription factor that directly binds the ALDOB promoter and activates ALDOB transcription; this regulation is upstream-controlled by METTL14-mediated m6A modification of FOXP3 mRNA (via IGF2BP1-dependent stabilization), linking RNA methylation to ALDOB expression and suppression of HCC glycolysis.\",\n      \"method\": \"Dual luciferase reporter assay, ChIP assay (FOXP3 binding to ALDOB promoter), MeRIP assay (m6A on FOXP3), RIP assay (METTL14/IGF2BP1 interaction with FOXP3), xenograft mouse models\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP and luciferase reporter, m6A modification by MeRIP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40778958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ALDOB is lactylated at lysine 87 (K87) under hypoxic conditions; K87 lactylation amplifies glycolytic flux and recruits DRP1 to mitochondria via SENP3-mediated deSUMOylation of DRP1, facilitating mitochondrial fragmentation and driving pulmonary artery smooth muscle cell proliferation, migration, and phenotypic switching in pulmonary hypertension; SIRT1 acts as the delactylase for ALDOB-K87.\",\n      \"method\": \"Lactylomic profiling, ALDOB lactylation-mimetic and -deficient mutants, DRP1 co-immunoprecipitation, SENP3 functional assays, rodent PH models, genetic/pharmacological suppression of ALDOB lactylation in vivo\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM identified by proteomics, validated by mutagenesis mimetics, protein interaction by Co-IP, in vivo disease model validation, single lab\",\n      \"pmids\": [\"41896623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALDOB overexpression in colorectal cancer enhances WNT signaling pathway-related proteins (β-catenin and c-myc), which promotes PDL1 expression in CRC cells, thereby inhibiting CD8+ T cell proliferation and killing activity in co-culture systems.\",\n      \"method\": \"ALDOB overexpression, western blot for β-catenin/c-myc/PDL1, co-culture assays with CD8+ T cells, flow cytometry\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach with downstream pathway western blot, no mechanistic resolution of how ALDOB engages WNT components\",\n      \"pmids\": [\"39909069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOB inhibition in hepatocellular carcinoma promotes upregulation of Ki67 and significantly enhances glycolytic activity, as well as proliferation, invasion, and migration of HCC cells; these effects are further amplified under hypoxic conditions, establishing ALDOB as a suppressor of glycolytic-driven malignant HCC behavior.\",\n      \"method\": \"ALDOB siRNA knockdown and overexpression in hepatoma cell lines, glycolytic activity assays, proliferation/invasion/migration assays under normoxia and hypoxia, in vivo animal tumor models\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined metabolic and cellular phenotypes, in vivo validation, single lab\",\n      \"pmids\": [\"36749124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FOXA2 transcriptionally activates ALDOB expression by binding the ALDOB promoter, enhancing fatty acid β-oxidation and suppressing irinotecan sensitivity in colorectal cancer; ALDOB overexpression restores drug resistance in FOXA2-inhibited cells.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP assay (FOXA2 binding to ALDOB promoter), FOXA2 knockdown/overexpression, ALDOB overexpression rescue, fatty acid β-oxidation rate assays, xenograft tumor model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP and luciferase, functional rescue with ALDOB overexpression, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41513047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Recombinant ALDOB variants p.R46W and p.Y343H show particularly impaired residual catalytic activity toward fructose-1-phosphate (F1P), establishing these residues as functionally important for enzymatic activity in aldolase B.\",\n      \"method\": \"Recombinant protein expression, enzymatic activity assay toward F1P\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with recombinant mutant proteins directly measuring catalytic activity, single lab\",\n      \"pmids\": [\"20848650\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALDOB is a fructose-1,6-bisphosphate aldolase that suppresses tumor growth through both enzymatic and non-enzymatic mechanisms: it forms a scaffold complex with Akt and PP2A to promote dephosphorylation and inactivation of p-Akt (independent of catalytic activity), translocates to the nucleus to interact with KAT2A and inhibit H3K9 acetylation at the TGFB1 promoter (suppressing immune evasion), and its expression is regulated epigenetically by SUV39H1-mediated H3K9me3 and transcriptionally by FOXP3, HNF4A, and FOXA2; additionally, ALDOB is post-translationally modified by lactylation at K87 (erased by SIRT1), which recruits DRP1 via SENP3-mediated deSUMOylation to drive mitochondrial fission, while in vascular tissue fructose-driven ChREBP activation and FoxO1/3α inactivation upregulate ALDOB to increase methylglyoxal production and vascular remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ALDOB is a fructose-1,6-bisphosphate aldolase whose catalytic handling of fructose metabolites and whose moonlighting protein-scaffold functions converge on a role as a metabolic gatekeeper and tumor suppressor [#0, #14]. Enzymatically it cleaves fructose-1-phosphate, an activity that depends on residues including R46 and Y343 [#14]; loss of this metabolic control allows F1P accumulation that drives hepatic de novo lipogenesis through GKRP and ChREBP [#7], and in vascular smooth muscle cells fructose-driven ChREBP activation with FoxO1/3α inactivation upregulates ALDOB to increase methylglyoxal output and proliferation [#4]. Beyond catalysis, ALDOB acts as a scaffold that recruits PP2A to dephosphorylate and inactivate Akt independent of enzymatic activity, an interaction abolished by the R304A mutant and suppressing tumor growth [#0, #8]. ALDOB also translocates to the nucleus, where it binds KAT2A to limit H3K9 acetylation at the TGFB1 promoter, repressing TGF-β and restraining Treg-mediated suppression of CD8+ T cells [#1]. Across hepatocellular, pancreatic, and gastric cancers, low ALDOB raises glycolytic flux, G6PD-driven pentose phosphate activity, and proliferation, identifying it as a suppressor of glycolytic malignancy [#2, #6, #12]. ALDOB expression is set epigenetically by SUV39H1-deposited H3K9me3 and transcriptionally by HNF4A, FOXP3, and FOXA2 [#6, #8, #9, #13]. Under hypoxia, ALDOB is lactylated at K87 (erased by SIRT1), which recruits DRP1 via SENP3-mediated deSUMOylation to promote mitochondrial fission and smooth muscle proliferation in pulmonary hypertension [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established which residues are required for ALDOB catalytic activity, defining the enzymatic basis later contrasted against non-catalytic moonlighting roles.\",\n      \"evidence\": \"Recombinant ALDOB variants assayed for F1P-cleaving activity in vitro\",\n      \"pmids\": [\"20848650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address substrate handling of fructose-1,6-bisphosphate\", \"No structural model of the active site provided\", \"No in vivo phenotype linked to these specific variants\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"First evidence that ALDOB engages a viral partner and influences survival signaling, hinting at non-metabolic protein-interaction functions.\",\n      \"evidence\": \"Yeast 2-hybrid and Co-IP of ALDOB with HBsAg, apoptosis pathway western blots in HepG2 cells\",\n      \"pmids\": [\"25072145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the complex modulates Akt/GSK-3β phosphorylation unresolved\", \"Direct vs indirect effect on Bcl-2 family proteins not separated\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that fructose-responsive transcription factors set ALDOB levels to control downstream methylglyoxal production, linking ALDOB to vascular remodeling.\",\n      \"evidence\": \"siRNA knockdown of ChREBP/FoxO, Akt1 inhibition, nuclear fractionation, fructose-fed mouse model\",\n      \"pmids\": [\"28007970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy of ChREBP at ALDOB not fully resolved\", \"Contribution of ALDOB enzymatic activity to MG production not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined ALDOB's catalysis-independent scaffolding role: it recruits PP2A to dephosphorylate p-Akt, establishing a tumor-suppressive non-enzymatic mechanism.\",\n      \"evidence\": \"Reciprocal Co-IP, R304A interaction-disrupting mutant, xenograft models, viability/glucose-uptake assays\",\n      \"pmids\": [\"33275593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ALDOB-Akt-PP2A scaffold unknown\", \"Determinants of complex assembly beyond R304 unmapped\", \"Tissue specificity of the scaffold not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a nuclear, chromatin-directed function for ALDOB, connecting it to immune evasion through KAT2A and TGFB1 repression.\",\n      \"evidence\": \"Co-IP, ChIP at TGFB1 promoter, nuclear fractionation, ALDOB knockout mouse tumor models, antibody blockade\",\n      \"pmids\": [\"38051951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering nuclear translocation of ALDOB unknown\", \"Whether KAT2A inhibition is direct enzymatic interference unresolved\", \"Genome-wide chromatin targets beyond TGFB1 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that low ALDOB reprograms glycolysis and the pentose phosphate pathway to confer chemoresistance, generalizing its tumor-suppressive metabolic role across cancers.\",\n      \"evidence\": \"PDAC organoid metabolomics, ALDOB gain-of-function rescue, GLUT1 inhibition, G6PD assays; parallel HCC siRNA/overexpression with glycolytic and invasion assays\",\n      \"pmids\": [\"37597521\", \"36749124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether metabolic effects require ALDOB catalysis vs scaffold function not separated\", \"Mechanism linking ALDOB loss to G6PD elevation incomplete\", \"Single-lab organoid systems\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified epigenetic and post-translational layers controlling ALDOB: SUV39H1-mediated H3K9me3 silencing, DUSP4-mediated dephosphorylation, and F1P-driven lipogenesis in its absence.\",\n      \"evidence\": \"ChIP for H3K9me3 at ALDOB promoter with rescue; IP-MS of DUSP4-ALDOB with G6PD readout; Aldob-/-;Gckr-/- mice with ChREBP knockdown and isotope tracing\",\n      \"pmids\": [\"39302619\", \"38843658\", \"38372975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Site of ALDOB phosphorylation targeted by DUSP4 not defined\", \"GKRP/ChREBP interventions did not reduce intrahepatic triglyceride, leaving lipid phenotype partly unexplained\", \"Cross-tissue generality of SUV39H1 silencing untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped the upstream transcriptional network activating ALDOB (HNF4A, FOXP3, FOXA2) and tied it to suppression of glycolysis, drug response, and Akt inhibition.\",\n      \"evidence\": \"ChIP and dual-luciferase promoter assays for HNF4A/FOXP3/FOXA2; Co-IP of ALDOB-AKT1; MeRIP/RIP for m6A control of FOXP3; rescue and xenograft models\",\n      \"pmids\": [\"39899681\", \"40778958\", \"41513047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each transcription factor in a given tissue unresolved\", \"Whether these regulators act combinatorially not tested\", \"FOXA2-driven β-oxidation link to ALDOB enzymatic function not isolated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovered hypoxia-induced K87 lactylation as a modification that couples ALDOB to mitochondrial fission machinery, expanding its role into pulmonary hypertension.\",\n      \"evidence\": \"Lactylomic profiling, lactylation-mimetic/-deficient mutants, DRP1 Co-IP, SENP3 assays, SIRT1 delactylase identification, rodent PH models\",\n      \"pmids\": [\"41896623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K87 lactylation mechanistically promotes DRP1 recruitment unresolved\", \"Whether this PTM affects the Akt/PP2A scaffold function unknown\", \"Single-lab disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ALDOB's enzymatic activity, cytoplasmic scaffolding of Akt/PP2A, and nuclear chromatin functions are coordinately controlled within a single cell and which is dominant in defined tissue contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating catalytic and scaffold conformations\", \"Signals partitioning ALDOB between cytoplasm, nucleus, and mitochondria undefined\", \"Catalysis-dependent vs -independent contributions to tumor suppression not cleanly separated across cancers\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 7, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AKT1\", \"PP2A\", \"KAT2A\", \"DUSP4\", \"DRP1\", \"HBsAg\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"ALDOB","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 38372975"},"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}